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BackgroundMany patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells.MethodsWe used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress.ResultsObese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH.ConclusionsIn heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.

Background: Early utilization of extracorporeal membrane oxygenation (ECMO) improves the clinical outcomes of patients with severe primary graft dysfunction (PGD3) after lung transplantation. Although there is a survival benefit, the impact of ECMO on airway complications has not been investigated. This study aims to describe the clinical association between posttransplant methods of support and the severity of acute airway anastomosis complications in patients with PGD3 following bilateral lung transplantation. Methods: Data from adult bilateral lung transplant patients diagnosed with PGD3 at our institution were retrospectively reviewed. Bronchial anastomosis necrosis (ischemia reperfusion injury [IRI]) that developed within a month after transplantation was graded. The data were compared among the groups of veno‐venous ECMO (VV‐ECMO) (n = 77), veno‐arterial ECMO (VA‐ECMO) (n = 14), and mechanical ventilation (MV, n = 33). Results: Higher levels of support (VV/VA‐ECMO) were associated with a lower incidence of PGD3, which was highest in recipients on MV only (M2 = 19.54, r = −0.41, p < 0.001). In a multivariable competing risk analysis, VV‐ECMO was protective against chronic allograft dysfunction (CLAD) relative to the MV group (HR: 0.36 [0.13–0.96], p = 0.042). There was no relationship between posttransplant support and survival. Conclusion: This study suggests posttransplant VV‐ECMO support in patients who develop PGD3 may confer a protective advantage over MV alone in the prevention of ischemic reperfusion injury. VV‐ECMO was associated with lower IRI grades and lower rates of BOS after transplantation. Future studies investigating the causal mechanisms are warranted. [ABSTRACT FROM AUTHOR]

The endothelial glycocalyx (eGC) is a carbohydrate‐rich layer on the vascular endothelium, and its damage can lead to endothelial and organ dysfunction. Heparanase (HPSE) degrades the eGC in response to cellular stress, but its role in organ dysfunction remains unclear. This study investigates HPSE's role in lung ischemia–reperfusion (I/R) injury. A left lung hilar occlusion model was used in B6 wildtype (WT) and HPSE genetic knockout (−/−) mice to induce I/R injury in vivo. The left lungs were ischemic for 1 h followed by reperfusion for 4 h prior to investigations of lung function and eGC status. Data were compared between uninjured lungs and I/R‐injured lungs in WT and HPSE−/− mice. WT lungs showed significant functional impairment after I/R injury, whereas HPSE−/− lungs did not. Inhibition or knockout of HPSE prevented eGC damage, inflammation, and cellular migration after I/R injury by reducing matrix metalloproteinase activities. HPSE−/− mice exhibited compensatory regulation of related gene expressions. HPSE facilitates eGC degradation leading to inflammation and impaired lung function after I/R injury. HPSE may be a therapeutic target to attenuate graft damage in lung transplantation. [ABSTRACT FROM AUTHOR]

Objective Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders significantly impacting skeletal muscles; however, the precise correlation between muscle magnetic resonance imaging (MRI) findings, muscle pathology, disease subtypes and clinical characteristics remains uncertain. Thus, we investigated the association of muscle MRI findings in IIMs with muscle pathology and clinical features. Methods New-onset IIM patients underwent proximal upper and/or lower limb muscle MRI. Patterns of muscle oedema on MRI were categorised into fascial, honeycomb, peripheral, foggy, dense, or coarse dot patterns and compared with inflammatory cell infiltration sites in corresponding muscle biopsies. The incidence of MRI patterns was examined in patient subgroups using myositis-specific antibodies (MSAs) and 2017 EULAR/ACR classification criteria. Univariate and multivariate analyses were conducted to determine the odds ratios (ORs) of MRI findings for clinical characteristics. Results Fifty-six of 85 patients underwent muscle biopsy. Foggy, honeycomb and fascial patterns at biopsy sites correlated with inflammatory cell infiltration in the endomysium (OR 11.9, P  = 0.005), perimysium (OR 6.0, P  = 0.014) and fascia (OR 16.9, P  < 0.001), respectively. Honeycomb and foggy patterns were characteristic of patients with anti-TIF1γ or anti-Mi2 antibodies and MSA-negative dermatomyositis, and those with anti-SRP or anti-HMGCR antibodies and MSA-negative polymyositis (PM), respectively. The honeycomb pattern positively correlated with malignancy (OR 6.87, P  < 0.001) and Gottron sign (OR 8.05, P  = 0.002); the foggy pattern correlated with muscle weakness (OR 11.24, P  = 0.005). The dense dot pattern was associated with dysphagia (OR 6.27, P  = 0.006) and malignancy (OR 8.49, P  = 0.002). Conclusion Muscle MRI holds promise in predicting muscle pathology, disease subtypes and clinical manifestations of IIMs. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to analyze the muscle magnetic resonance imaging (MRI) findings of patients with antineutrophilic cytoplasmic antibody‐associated vasculitis (AAV) and polyarteritis nodosa (PAN) presenting with clinical symptoms in the extremities. Methods: Retrospective analysis was conducted on short tau inversion recovery MRI findings, with a focus on intramuscular vessels displaying abnormal perivascular signals, in 22 and eight patients with AAV and PAN, respectively. The number per unit area (4 cm2) and diameter of abnormal vessels on muscle MRI were compared between patients with AAV and those with PAN. Cut‐off values, clinical sensitivity, and specificity for these indices were calculated from the receiver operating characteristic curves to distinguish between AAV and PAN, and the relationship between the indices and clinical findings in AAV was analyzed. Results: The number of abnormal vessels per unit area was significantly higher in AAV compared to PAN (p <.05). Additionally, the diameter of the abnormal vessels was significantly higher in PAN than in AAV (p <.05). The presence of >6.44 abnormal vessels per unit area or ≤3.61 mm diameter of abnormal vessels was able to predict AAV (sensitivity, 0.955; specificity, 0.625). AAV patients with peripheral neuropathy exhibited a significantly higher number of abnormal vessels per unit area than those without peripheral neuropathy (p <.05). Conclusions: Muscle MRI can detect small‐ to medium‐vessel vasculitis and be a valuable tool for distinguishing between patients with AAV and PAN experiencing clinical symptoms in the extremities. [ABSTRACT FROM AUTHOR]

This article discusses a case report of a patient who developed peristomal pyoderma gangrenosum (PG) while being treated with TNF-α inhibitors for rheumatoid arthritis (RA) and Behçet's disease (BD). Despite treatment with various medications, the patient's ulcers persisted and worsened. However, when the patient was switched to baricitinib, a Janus kinase (JAK) inhibitor, both the RA and the PG improved. The article suggests that JAK inhibitors may be an alternative treatment option for patients with PG who do not respond to TNF-α inhibitors. [Extracted from the article]

The teleoperation feature of a leader–follower robot is used to operate the robot in a working environment that is dangerous to the operator. This paper proposes a method for estimating the intended operation of the operator of the leader–follower robot and generating behaviors for the follower robot. By generating partially autonomous robot behavior, our proposed method decreases the burden on the operator and realizes a safe controller that is robust against misoperation or disturbances. Owing to the impact of misoperation on estimation and the potential for unintended movement of the follower robot, our proposed estimation method relies on historical values of intended operation. The proposed method was verified through simulation using real operation inputs to the leader system based on practical scenarios, including misoperation. [ABSTRACT FROM AUTHOR]